Project summary This continuation renewal seeks support for years 6-10 for our Center of Biomedical Research Excellence (COBRE) in Oxidants, Redox Balance, and Stress Signaling at the Medical University of South Carolina (MUSC). Investigator projects focus on human pathologies that include many of the perceived strengths of MUSC including, cancer, cardiovascular disease, neurodegenerative disorders and drug/alcohol addiction and have additional components of drug discovery and development. In each instance the interface of these diseases with oxidant stress, redox homeostasis and stress signaling provides the fundamentals for the programmatic development of the Center. We plan to develop these assets further via clusters of 5 projects and 5 Cores involving 10 established scientists from 4 academic disciplines, with project Directors being from 4 different departments from 2 colleges. Because of increased demand and at the behest of our EAC, we have added a new core (Analytical Redox), in concert to the existing facilities (Proteomics, Cell and Molecular Imaging, Bioenergetics Profiling, Administrative). The COBRE has a number of faculty members who have graduated following successful grant awards garnered in years 1-4, most of whom remain affiliated with the program. Research projects for the five target mentees cover: resistance to drugs that target the proteasome in multiple myeloma, redox regulation of cancer stem cell growth, ROS in mitochondrial anion channel functions, ROS in mitochondrial function in aortic valve stenosis and antioxidants in vagus nerve stimulation in Parkinson's disease. Mentoring and career development efforts also provide critical mass in sustaining scientific growth and development of independent research careers through the COBRE. As with the previous period as junior faculty members achieve success, there are plans for the COBRE Directors to recruit between 3 and 6 individuals over the next five years, providing a cadre of new investigators eligible for the COBRE program. This COBRE includes cross-college and inter-department collaborations, with the Directors having leadership roles in the Colleges of Medicine and Pharmacy, the Hollings Cancer Center and South Carolina Center for Therapeutic Discovery and Development. This incorporates the recruitment of endowed chairs that can participate as mentors and laboratory space in the Drug Discovery Building. During Phase I, we have partnered with COBRE's from the University of South Carolina (USC) and Nebraska to foster teaching, research collaborations and technical expertise. Our Phase II COBRE will continue to emphasize the efforts of junior faculty, to expand and sharpen their research programs. Independent research projects and proposals, robust interactions among established investigators in oxidative stress signaling, along with effective mentoring will continue to be the overriding goals for this COBRE renewal.